Activity Variations of CYP2B6 Determine the Metabolic Stratification of Efavirenz.

IF 3.7 3区医学 Q2 CHEMISTRY, MEDICINAL Chemical Research in Toxicology Pub Date : 2024-10-14 DOI:10.1021/acs.chemrestox.4c00230

Xin-Yue Li, Qian Liu, Xiao-Yu Xu, Jing Wang, Yun-Shan Zhong, Le-Hao Jin, Jing Yuan, Jian-Chang Qian, Xiao-Dan Zhang

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Abstract

Purpose: To investigate the effects of hepatic enzyme activity variations and CYP2B6 gene polymorphisms on the in vivo and in vitro metabolism of efavirenz.

Main methods: In vitro enzyme systems using rat and human liver microsomes (RLM/HLM) were established, with in vivo studies conducted on Sprague-Dawley rats. Metabolite detection was performed via LC-MS/MS. Human recombinant CYP2B6 microsomes were prepared using a baculovirus-insect cell system and ultracentrifugation, with efavirenz serving as the substrate to study enzyme kinetics.

Results: Isavuconazole exhibited an IC₅₀ of 21.14 ± 0.57 μM in RLM, indicating a mixed competitive and noncompetitive mechanism, and an IC₅₀ of 40.44 ± 4.23 μM in HLM, suggesting an anticompetitive mechanism. In rats, coadministration of efavirenz and isavuconazole significantly increased the AUC, T_max, and C_max of efavirenz. Co-administration of efavirenz and rifampicin significantly elevated the AUC, T_max, and C_max of 8-OH-efavirenz. The activity of CYP2B6.4, 6, and 7 increased significantly compared to CYP2B6.1, with relative clearance ranging from 158.34% to 212.72%. Conversely, the activity of CYP2B6.3, 8, 10, 11, 13-15, 18-21, 23-27, 31-33, and 37 was markedly reduced, ranging from 4.30% to 79.89%.

Conclusion: Variations in liver enzyme activity and CYP2B6 genetic polymorphisms can significantly alter the metabolism of efavirenz. It provides laboratory-based data for the precise application of efavirenz and other CYP2B6 substrate drugs.

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目的：研究肝酶活性变化和 CYP2B6 基因多态性对依非韦伦体内和体外代谢的影响：主要方法：利用大鼠和人类肝脏微粒体（RLM/HLM）建立体外酶系统，并在Sprague-Dawley大鼠身上进行体内研究。代谢物检测通过 LC-MS/MS 进行。利用杆状病毒-昆虫细胞系统和超速离心法制备了人重组 CYP2B6 微粒体，以依非韦伦为底物研究酶动力学：伊沙夫康唑在 RLM 中的 IC50 为 21.14 ± 0.57 μM，表明存在竞争和非竞争混合机制；在 HLM 中的 IC50 为 40.44 ± 4.23 μM，表明存在反竞争机制。在大鼠体内，依非韦伦和异武康唑同时给药可显著增加依非韦伦的AUC、Tmax和Cmax。依非韦伦和利福平同时给药可明显提高 8-OH-efavirenz 的 AUC、Tmax 和 Cmax。与 CYP2B6.1 相比，CYP2B6.4、6 和 7 的活性明显增加，相对清除率为 158.34% 至 212.72%。相反，CYP2B6.3、8、10、11、13-15、18-21、23-27、31-33 和 37 的活性明显降低，降低幅度为 4.30% 至 79.89%：肝酶活性和 CYP2B6 基因多态性的变化可显著改变依非韦伦的代谢。它为依非韦伦和其他 CYP2B6 底物药物的精确应用提供了实验室数据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Chemical Research in Toxicology 医学-毒理学

CiteScore

7.90

自引率

7.30%

发文量

215

审稿时长

3.5 months

期刊介绍： Chemical Research in Toxicology publishes Articles, Rapid Reports, Chemical Profiles, Reviews, Perspectives, Letters to the Editor, and ToxWatch on a wide range of topics in Toxicology that inform a chemical and molecular understanding and capacity to predict biological outcomes on the basis of structures and processes. The overarching goal of activities reported in the Journal are to provide knowledge and innovative approaches needed to promote intelligent solutions for human safety and ecosystem preservation. The journal emphasizes insight concerning mechanisms of toxicity over phenomenological observations. It upholds rigorous chemical, physical and mathematical standards for characterization and application of modern techniques.